Depression is an important risk factor for CVD both in medically healthy individuals and those with a history of heart disease. Several homeostatic changes are common to both these disorders, including increased heart rate and decreased heart rate variability (HRV). However, the mechanisms underlying this relationship are not well understood. Oxytocin (OT) is thought to be involved in this association as it plays a role in both emotion/mood and cardiovascular homeostasis. OT has anti-stress properties and modulates the expression of antidepressant- and anxiolytic-like behaviors in both humans and non-human animals. Additionally, OT has been shown to reduce pulse rate and blood pressure suggesting that OT may be cardiac protective. The primary aim of the current proposal is to investigate the hypothesis that neural mechanisms involving OT mediate the link between depression and CVD. This research plan proposes to take advantage of a unique rodent system, the monogamous prairie vole (Microtus ochrogaster), to investigate behavioral, neuroendocrine, and cardiovascular responses to a species-relevant and translational stressor, social isolation. Like humans, prairie voles develop negative affective behaviors (relevant to depression and anxiety) when exposed to chronic isolation. Isolated prairie voles also display cardiac dysfunction similar to that of depressed humans, including increased heart rate, decreased HRV, and altered cardiac responses to stressors. OT levels are elevated in isolated voles and OT treatment attenuates depressive-like affect and cardiovascular dysfunction in isolated individuals. To test the above hypothesis, OT receptors will be antagonized to determine if the lack of OT receptor stimulation will increase susceptibility to the deleterious effects of prolonge social isolation. Specifically, this research will 1) use validated behavioral assays of negative affect (e.g., forced swim test) to determine the behavioral response to social isolation and an OT antagonist (OTA), 2) use cardiac monitoring technology to record the effects of social isolation and OTA on cardiovascular function, and 3) investigate the effect of isolation and OTA on OT receptor binding (via receptor autoradiography) and gene expression (via RT-PCR) in brain regions associated with mood and autonomic function as well heart tissue. Collectively, these experiments will provide valuable information about mechanisms underlying the link between CVD and depression. The completion of the proposed research will provide an important step in the applicant's (Melissa-Ann Scotti's) long-term goal of developing and using translational animal models to provide further understanding of and improve human physical and mental health. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) is the dominant cause of death in the United States. Depression is an important risk factor for CVD and symptoms of depression predict an increase in fatal and non-fatal heart disease in medically well individuals regardless of other baseline medical variables such as smoking, and obesity. The research proposed here will explore the link between these disorders, providing further insight into the treatment and prevention of heart disease.